© 2013 ILEX PUBLISHING HOUSE, Bucharest, Roumania
http://www.jrdiabet.ro
Rom J Diabetes Nutr Metab Dis. 20(3):343-352
doi: 10.2478/rjdnmd-2013-0034
NEONATAL DIABETES – FROM GENE DISCOVERY
TO CLINICAL PRACTICE CHANGES
Cristian Guja 1, , Loreta Guja 2, Constantin Ionescu-Tîrgovişte 1
1
2
National Institute of Diabetes, Nutrition and metabolic Diseases “Prof. NC Paulescu”,
Bucharest, Romania
“Lotus” Medical Center, Bucharest, Romania
received:
July 25, 2013
accepted:
August 19, 2013
available online:
September 15, 2013
Abstract
Diabetes mellitus is one of the most common chronic diseases but also one of the most
heterogeneous. Apart the common phenotypes of type 1 and type 2 diabetes, around 1-2%
of all cases arise from a single gene mutation and are known as monogenic diabetes.
Diabetes diagnosed within the first 6 months of life is known as neonatal diabetes and has
been extensively studied during the last two decades. Unraveling the genetic cause and
molecular mechanism of this rare diabetes phenotype led to a dramatic change in the
treatment of these children who often can be switched from insulin to sulphonylurea
treatment. The aim of this paper is to review the known genetic causes of neonatal
diabetes and to highlight the most recent aspects of the disease caused by mutations in the
KATP and insulin genes, with a special focus on the individualized treatment of these
cases.
key words: neonatal diabetes, KCJN11, ABCC8, insulin gene, sulphonylurea
million subjects. Unfortunately, the epidemic of
Introduction
diabetes affects also children, with significant
Diabetes mellitus is one of the most increases in incidence for both type 1 (T1DM)
common chronic diseases in human populations and type 2 (T2DM) diabetes.
across the globe. Thus, the 2012 update to the
During the last decades, major progresses
Fifth Edition of the International Diabetes have been made in unraveling the genetics of
Federation (IDF) Atlas published in 2011 reports diabetes for both the two major diabetes
that currently 371 million people have diabetes phenotypes, the polygenic forms of T1DM and
[1]. Moreover, the prevalence of diabetes T2DM. These genetic studies have led also to
continues to rise in both the Western world and the precise description of the rare forms of
in the developing countries as changing lifestyles diabetes with exclusively genetic pathogenesis
lead to reduced physical activity, and increased known as monogenic diabetes, including
obesity. The same 2011 IDF Atlas [1] predicts neonatal diabetes mellitus (NDM) and maturity
that the prevalence of diabetes will reach number onset of diabetes in young (MODY). These were
will reach almost 10% by 2030, meaning ~552 included in the last classification of diabetes [2]

 5-7 Ion Movila Street, Bucharest 2, Romania; Tel: 004 021 210.84.99; Fax: 004 021 210.22.95;
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in group 3 - Other Specific Types of Diabetes,
subgroup 1 - Genetic defects of the β-cell. As we
shall further discuss below, monogenic diabetes
provided a unique opportunity for using genetics
to improve the care and treatment of patients.
Neonatal diabetes – Definition
and clinical forms
Diabetes in neonates and infants has been
first described more than two centuries ago [3]
but before the discovery of insulin by Nicolae
Paulescu in 1921 these infants did not survive.
After insulin discovery, the number of NDM
cases surviving till adulthood increased, so that
in the 1950s series of tens of cases followed up
for more than 10 years were reported [4]. In
parallel with the deciphering of the autoimmune
nature of T1DM and the advent of beta cell autoantibodies testing, clinicians have begun to
suspect a distinct underlying etiology for NDM
[5].
Currently, diabetes clinically diagnosed
within the first 6 months of life is defined as
neonatal diabetes mellitus [6-8]. Depending on
whether diabetes resolves later in life or is
permanent throughout life, two phenotypes were
described: Permanent neonatal diabetes (PNDM)
or transient neonatal diabetes (TNDM).
TNDM accounts for approximately for 50%
cases of NDM, with an incidence of ~1/100,000
live births [9]. Its main clinical feature is that it
may either spontaneously remit or be so mild as
not to require treatment. However, usually
diabetes will often relapse, most often during
adolescence [10]. The majority (about 80%) of
cases of TNDM are caused by abnormalities of
an imprinted locus on chromosome 6q24 that
results in the over-expression of a paternally
expressed gene [11]. PNDM accounts for the
other 50% of NDM cases. Although the majority
of cases of PNDM involve isolated diabetes,
some of the known monogenic causes are
characterized by a variety of syndromic features.
344
Main genetic defects leading to NDM or
congenital syndromes including diabetes
There are five main classes of β-cell
dysfunction that encompass most cases of
monogenic diabetes [6]: 1) Defective glucose
sensing (Glucokinase - GCK gene); 2) Abnormal
potassium ATP-sensitive (KATP) channels
(KCNJ11 - Potassium channel (subfamily J)
member 11 and ABCC8 - Sulfonylurea Receptor
genes); 3) Mutated transcription factors
(Hepatocyte Nuclear Factors HNF-4α, HNF-1α,
HNF-1β, IPF-PDX1, NEUROD1, etc); 4)
Defective mitochondria (A3243G mutation in
mitochondrial DNA) and 5) Endoplasmic
reticulum stress (EIF2AK3 - Pancreatic EIF2
alpha kinase, INS – insulin gene, WFS1 –
Wolframin gene). The identification of the
etiological genes helped the recognition of novel
clinical subgroups, including neonatal diabetes
or genetic syndromes that include neonatal
diabetes. A brief description of these syndromes
is given in Table 1.
It should be stated that a form of PNDM can
be induced also by homozygous mutation in all
the MODY genes. Homozygous mutations in
IPF-PDX1 and NEUROD1 lead to pancreatic
agenesis with permanent diabetes accompanied
by signs of exocrine pancreatic insufficiency.
Transient Neonatal Diabetes Mellitus
TNDM is characterized by severe
intrauterine growth retardation (due to deficient
insulin secretion in utero) and diagnosis of
diabetes within days from birth [12]. It was the
first form of NDM for which the genetic basis
was unraveled. Most often, TNDM is induced by
the overexpression of some paternally imprinted
genes located on chromosome 6q24 [13]. Most
often involved is over-expression of the genes
PLAGL1/ZAC (pleiomorphic adenoma genelike 1) and HYMAI (hydatidiform mole associated and imprinted transcript), whose exact
function is still not fully elucidated [14]. The
Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 20 / no. 3 / 2013
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expression of these genes is normally restricted
to the paternal allele as a result of maternal DNA
methylation. More recently it was shown that
TNDM is not associated with mutations of the
PLAGL1 or HYMAI genes, but rather with their
overexpression
via
uniparental
disomy,
chromosome duplication, or relaxation of
imprinting [15]. The main cause seems to be a
defect in maternal methylation, most often due to
recessive mutations in the ZPF57 (Zinc Finger
Protein) gene [13,15,16]. The treatment of
TNDM cases classically relied on insulin. More
recently, some attempts of sulfonylurea
treatment have been made [17]. Data on the
largest case-series of 6q24 TNDM, including
163 patients from Europe, the Americas, Asia
and Australia, were recently published [12].
Less frequent causes of TNDM are
represented by mildly activating mutations in the
genes encoding the KATP channel KCJN11 and
ABCC8 but in these cases the clinical picture is
dominated
by
repeated
episodes
of
hyperglycemia that require intermittent treatment
during childhood [18].
Table 1. Neonatal diabetes and other rare monogenic syndromes including diabetes (adapted after [6]).
Disease
TNDM
PNDM
Gene
PLAGL1
(ZAC)
Locus
KCNJ11
11p15.1
ABCC8
(SUR1)
11p15.1
Sulfonylurea Receptor
KCNJ11
11p15.1
Potassium channel
(subfamily J, member
11)
11p15.1
Sulfonylurea Receptor
11p15.5
Insulin gene
7p15-p13
Glucokinase
ABCC8
(SUR1)
INS
GCK
(homozygo
us)
6q24
Detailed name
Pleomorphic adenoma
gene-like 1
Potassium channel
(subfamily J, member
11)
Mitochondrial
diabetes
mtDNA
mt3243A>
G
Mitochondrial DNA
Wolfram
Syndrome
WFS1
4p16.1
Wolframin
WolcottRalisson
Syndrome
EIF2AK3
(PERK)
2p12
Pancreatic EIF2
alpha kinase
Permanent Neonatal Diabetes Mellitus
PNDM may be either isolated or form part
of a syndrome associating diabetes and other
extra-pancreatic manifestations, as briefly
described in Table 1. The most common causes
Clinical features
Intrauterine growth retardation, acute
onset diabetes, insulin treatment,
remission between 3-6 months, usually
relapses later in life
Intrauterine growth retardation (IUGR),
acute onset diabetes, insulin treatment,
KCNJ11 and ABCC8 types can be
treated successfully with high dose
sulphonylurea therapy, usually with
better results than insulin
Maternally inherited, usually diagnosed
later in life, almost all carriers develop
diabetes, 75% deafness, increased risk
for stroke, epilepsy, renal and cardiac
disease
Childhood onset; associates optic
atrophy, deafness, diabetes insipidus,
gonadal atrophy, neurological and
psychiatric disease. Median age at death
is 30 years.
Childhood onset, associates epiphyseal
dysplasia, renal and hepatic dysfunction
and mental retardation. Most cases do
not survive beyond 15 years.
of isolated PNDM are represented by mutation
in the genes that encode the KATP channel
components Kir6.2 (KCJN11 gene) and
Sulphonylurea Receptor – SUR (ABCC8 gene)
on chromosome 11p15.1 and insulin (INS gene)
on chromosome 11p15.5 [9].
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345
PNDM due to KCJN11 mutations
The pancreatic beta cell KATP channel is an
octamer complex formed by four Kir6.2
(Potassium Inward Rectifier 6.2) subunits and
four regulatory SUR1 (Sulphonylurea Receptor1) subunits [19]. Kir6.2 is an inwardly rectifying
K-channel that forms the potassium-selective
pore and possesses an inhibitory site for ATP.
SUR1 is a member of the ATP binding cassette
(ABC) superfamily and plays multiple
regulatory roles [9,20]. At low glycemic levels,
the KATP channels from the beta cell membrane
are open and a continuous efflux of potassium
through the channel keeps a negative potential of
the beta cell membrane, with the consequent
closure of the voltage dependent calcium
channels [21]. When blood glucose levels rise, it
is transported inside the beta cell through
specific glucose transporters and subsequently
metabolized, a process that increases the ATPto-ADP ratio. This leads to closure of the KATP
channel which stops the K+ efflux with
subsequent membrane depolarization which
leads to the opening of the voltage dependent
calcium channels and Ca2+ influx in the beta cell.
Finally, increased calcium levels inside the beta
cell induce exocytosis of the insulin granules.
Due to the key role of the KATP channel for
insulin secretion, it was hypothesized that
mutations in the genes encoding its two
components might lead to disease states
characterized either by hypo or hyperglycemia
[22]. In fact, it was already known that loss of
function mutations in both KCJN11 and ABCC8
genes can cause over-secretion of insulin and
lead to the congenital hyperinsulinism of infancy
(CHI) [23]. Actually more than 100 mutations of
the KATP channel associated with CHI have been
described. Most these mutations result in nonfunctional channels associated with continuous
depolarization of the beta cell membrane and
subsequent excessive and un-regulated insulin
secretion [24]. Based on these facts, it was
346
hypothesized that the opposite state – overactive
KATP channels induced by gain of function
mutations in the KCJN11 and ABCC8 genes –
might be associated with diabetes mellitus [25].
Such mutations will block the KATP channels in
an opened state maintaining the beta cell
membrane hyperpolarized, thus preventing the
Ca2+ influx and impairing insulin secretion.
The hypothesis was first confirmed in 2004
by Anna Gloyn and colleagues who reported
PNDM caused by activating dominantlyinherited mutations in the KCJN11 gene [26]. In
this article it was shown that 10 out of 29
patients with PNDM had heterozygous
mutations in this gene. The number of mutations
increased continuously so that currently more
than 30 are described as being associated with
PNDM [27]. All KCJN11 gene mutations
associated with PNDM are heterozygous.
Depending on their location, they affect either
ATP mediate closure of the channel alone (with
lower KATP electric currents) or combined with a
defect in channel gaiting and channel
conformation which keeps it opened (usually
associated with higher KATP electric currents)
[20,28]. In addition, depending on the severity of
the mutations, function of the KATP channels in
other tissues (mainly neuronal) can be altered.
Patients carrying KCJN11 mutations can be
classified in four distinct clinic phenotypes,
usually dependent on the severity of the
mutations. The most frequent are isolated NDM,
usually PNDM but, more rarely, TNDM also
[9,20]. The most severe disease phenotype is
known as the Developmental Delay, Epilepsy
and neonatal Diabetes Syndrome (DEND).
These patients exhibit also severe neurological
impairment, including motor development delay,
muscle weakness, epilepsy and dismorphic
features [28,29]. Finally, some patients have an
intermediate phenotype between isolated PNDM
and DEND. These are considered to have the
intermediate DEND known as iDEND and are
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characterized by some degree of motor
development delay (usually by 1-2 years),
muscle weakness and late development of
speech [30]. Specific KCNJ11 mutations
associated with iDEND have been described
[31].
PNDM due to ABCC8 mutations
Mutations of the ABCC8 gene (encoding for
the SUR1 component of the KATP channel) that
cause PNDM were first identified in 2006,
almost simultaneously, by the groups of Proks et
al. [32] and Babenko et al. [33]. Most subjects
carrying ABCC8 mutations have isolated PNDM
or, more rarely, TNDM. Up to 30% of patients
have additional neurological features, including
developmental delay,
muscle weakness,
epilepsy, learning difficulties, etc. [18,34], up to
the most severe form of DEND [9]. To date,
only two ABCC8 mutations (F132L and I49F)
were identified to be associated with the DEND
syndrome [9] while one mutation (L213R) with
the iDEND [33].
Currently over 60 mutations of the ABCC8
gene have been identified. All are missense
mutations, can be either heterozygous
(dominant) or homozygous (recessive). They
account for more than 10% of PNDM cases and
sometimes for TNDM [35]. Generally no
correlation was found between the location of
the ABCC8 mutations and the clinical
phenotype.
PNDM due to INS mutations
Heterozygous
autosomal
dominantly
inherited mutations in the insulin gene (INS) are
the second most common cause of PNDM (after
mutations in KCNJ11) [10]. Thus, in the large
Prof. Hattersely Exeter cohort of PNDM
subjects, ~14% of patients were found to carry
INS mutations [36]. Sometimes the diagnosis of
diabetes is made after 6 months of age which is
the limit of diagnosis of PNDM. INS mutations
associated with PNDM were identified
independently by the groups of Støy et al. in
2007 [37] and Colombo et al. in 2008 [38].
Most often INS mutations associated with
PNDM are heterozygous mutations that
determine the synthesis of a preproinsulin or
proinsulin molecule with structural abnormalities
[39]. The probable mechanism of diabetogenesis
involves β-cell endoplasmic reticulum stress
secondary to the misfolding of the proinsulin
encoded by the mutated alleles. This is explained
by the altered formation of the disulfide-bonds
between the A-chain and B-chain of the
proinsulin molecule. The misfolded protein does
not progress normally through the endoplasmic
reticulum, finally impairing the normal beta cell
function and leading to beta cell death [39]. This
mechanism has been repeatedly demonstrated
both in vitro and in animal models [40,41].
Less frequently, recessive homozygous
mutations in INS can affect proinsulin
biosynthesis per (via different mechanisms
including deletion of exons, decreased
transcription or translation) and finally lead to
NDM [42]. Finally, it should be mentioned that
INS mutations have been reported to be
associated also with infancy-onset diabetes
(between 6 and 12 months of age, nonautoimmune T1DM, MODY and early onset
T2DM [39].
Congenital syndromes including
infancy/childhood onset diabetes
The extensive investigation of the
monogenic forms of diabetes during the last two
decades has led to the identification of an
expanding list of causal genes inducing
congenital diabetes associated with other nondiabetic phenotypic features. The list includes
syndromes for which diabetes is diagnosed
beyond the neonatal period but frequently in
early infancy and this is the reason for including
them in our review. Despite the fact they are
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347
very rare, considering these clinical entities in
the differential diagnosis of diabetes in early
infancy is important. This is why, a complete list
of these syndromes, including the genetic defect
and main clinical features are given in Table 2.
Table 2. Monogenic forms of diabetes occurring during early infancy accompanied by syndromic features.
(Adapted after [10]).
Gene
Locus
RFX6
6q22.2
IER3IP1
18q21.
1
Immediate early response 3
interacting protein 1
NEUROG3
10q21.
3
NeuroG3 or Neurogenin 3/
bHLH transcription factor
NEUROD1
2q32
(Neurogenic Differentiation 1)
/bHLH transcription factor
PTF1A
10p12.
3
GLIS3
9p24.3
PDX1
13q12.
1
HNF1B
17q12
PAX6
11p13
WFS1
4p16.1
Wolframin
1q23.3
Thiamine
1/transports
thiamine across
membrane
SLC19A2
Detailed name/function
DNA-binding protein (RFX6)/
winged-helix
transcription
factor
Pancreas transcription factor 1,
subunit α/ bHLH transcription
factor
Glioma-associated oncogenesimilar family zinc finger 3
(GLIS3)/ transcription factor
Pancreas/duodenum homeobox
protein 1 /transcription factor
Hepatocyte nuclear factor 1β
/transcription factor
Paired box gene / transcription
factor
transporter
the
plasma
SLC2A2/
GLUT2
3q26.1
GLUT2/facilitative glucose
transporter
FOXP3
Xp11.2
3
Forkhead box protein P3/
transcription factor
EIF2AK3
(PERK)
2p12
Pancreatic EIF2
alpha kinase
From gene discovery to paradigm shift in
the treatment of PNDM
PNDM has been treated invariably with
insulin before the era of modern genetics. In fact,
until then it was not distinguishable from the
348
Clinical features
Diabetes diagnosed within the first days of life,
pancreatic hypoplasia, intestinal atresia, gall bladder
agenesis/hypoplasia, and congenital diarrhea
Neonatal diabetes with simplified gyral pattern
microcephaly and severe infantile-onset epileptic
encephalopathy.
Diabetes and chronic intractable malabsorptive
diarrhea starting soon after birth
NDM, small for gestational age, cerebellar
hypoplasia, developmental delay, sensorineural
deafness, and visual impairment.
Congenital diabetes, paucity of subcutaneous fat,
optic nerve hypoplasia, complete agenesis of the
cerebellum and complete absence of the pancreas,
NDM within the first few days of life, low birth
weight, mild facial dysmorphism, and congenital
primary hypothyroidism
PNDM and exocrine dysfunction following pancreatic
agenesia
NDM, dysplastic kidneys (without cysts or
evidence of renal failure), pancreatic hypoplasia
NDM, brain malformations, microcephaly, and
microphthalmia
Childhood onset; associates optic atrophy, deafness,
diabetes insipidus, gonadal atrophy, neurological and
psychiatric disease. Median age at death is 30 years.
Thiamine-responsive megaloblastic anemia (Rogers
syndrome), infancy diabetes, sensorineural deafness
Hepatic and renal glycogen accumulation; renal
proximal tubular dysfunction, glycosuria, phosphate
wasting, rickets, delay of puberty and short stature;
hypergalactosemia; mild fasting hypoglycemia but
postprandial hyperglycemia and diabetes or impaired
glucose tolerance
Neonatal
monogenic
autoimmune
diabetes,
enteropathy, severe diarrhea and malnutrition, severe
eczema, autoimmune thyroid disease.
Childhood onset, associates epiphyseal dysplasia,
renal and hepatic dysfunction and mental retardation.
Most cases do not survive beyond 15 years.
common form of autoimmune T1DM, patients
being assumed to suffer from this disease.
Recognition of the fact that approximately 2/3 of
PNDM patients carry mutations in the KATP
channel subunits [35,36] led to the hypothesis
that these subjects might be treated with
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sulphonylureas (SUs) instead of insulin. The
hypothesis was based on the fact that SUs bind
to both Kir6.2 and SUR1 subunits of the KATP
channel, though with very different affinities:
high for SUR1 and low for Kir6.2 [9].
Subsequently, studies of the mutant proteins in
vitro confirmed this hypothesis [3], followed
quickly by isolated case reports [43] and small
clinical series [44,45] proving the efficacy of SU
treatment in cases of PNDM caused by KCJN11
gene mutations. The precise molecular
mechanism of the SU block of mutant KATP
channels was reviewed recently [46].
The largest series of PNDM treated
successfully with SUs was published in 2006
[47] and included 49 subjects. In this study, 90%
of the patients successfully discontinued insulin
after switch to SUs, while HbA1cd improved in
all patients, (from 8.1 percent before treatment to
6.4 percent after 12 weeks of treatment,
P<0.001). Subsequently, studies showed the
success of SU treatment in most cases of PNDM
secondary to SUR1 mutations [48]. The most
commonly used drug for the treatment of PNDM
is glibenclamide (glyburide). The usual dose
used is 0.4-1 mg/kg/day which is higher than the
current dose used for the treatment of T2DM
[43,47,48]. However, the improvement in the
quality of life of the patients and families is
heartbreaking. Interestingly, patients continue to
maintain near normal HbA1c for years after
switching to SU treatment [49]. Even more, the
incidence of hypoglycemia in these patients
seems to be very low, with no cases of severe
hypo’s reported even in patients receiving very
high doses (> 2 mg/kg) of glibenclamide [3].
However, long-term monitoring of the PNDM
cases treated with SUs will be required in order
to assess the safety of these drugs on the long
term.
It should be mentioned though that there is a
group of patients with PNDM due to KATP
channel mutations that do not respond to SU
treatment. It includes the patients who are older
at the time of insulin/SU switch attempt [3] and
those with DEND syndrome [50]. For the former
category, the probable explanation is the
progressive decline in functional beta cell mass
over time, so that SU “rescue” of beta cell
function on a decreased beta cell mass is not
enough to restore efficacious insulin response
[47].
Although it is not clear to what extent SUs
can cross the blood-brain barrier, several case
report studies reported improvements in
neurological disabilities of the patients with
DEND syndrome following SU treatment
[51,52]. Usually these are cases of iDNED,
require higher doses of glibenclamide (up to 2.3
mg/kg/day) and none exhibit complete resolution
of the neurologic disorders. However, the
improvements in both glucose control and neurodevelopmental outcome warrants at least
attempting SU treatment in these cases [3].
Conclusions
Major progresses have been made in
deciphering the genetics of monogenic diabetes.
Unraveling the molecular mechanism leading to
PNDM led to a paradigm shift in the treatment
of cases associated with mutations in the KATP
channel. SU treatment in these cases is not only
more efficacious but also safer and associated
with greatly improved quality of life for the
children and their families. Deciphering the
exact genetic mechanisms will be hopefully
useful in establishing the most appropriate
treatment of the rare recessive monogenic forms
of diabetes associated with other syndromic
features. Finally, the study of monogenic
diabetes provides a unique opportunity to
elucidate the beta cell function.
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349
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